Gaseous f-18 technologies

ABSTRACT

Methods, compositions, and systems related to preparing gaseous  18 F-compounds for use in radiolabeling positron emission tomography (PET) tracer precursor compounds are disclosed. [ 18 F]fluoride ions produced by conventional methods are converted by reaction with an acid anhydride having the formula: to a gaseous  18 F-compound having the formula: wherein each R is independently a substituted or unsubstituted, straight chain or branched CrC4 alkyl group. The resulting gaseous  18 F-compounds can be produced and stored in close proximity to the production location of the [ 18 F]fluoride ions (such as within a cyclotron vault), or easily and efficiently transported long distances with minimal loss of-radioactivity. The gaseous  18 F-compounds, which also can be readily trapped on solid-phase extraction media or in organic solvents such as acetonitrile, provide an alternative source of [ 18 F]fluoride for use in the nucleophilic substitution reactions that are used to synthesize a large number of  18 F-labeled PET imaging tracers, including 2-[ 18 F]fluoro-2-deoxyglucose (FDG).

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is based on, claims the benefit of, and incorporatesherein by reference U.S. Provisional Patent Application No. 61/954,839filed Mar. 18, 2014.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Not Applicable.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The field of the invention is the manufacture of ¹⁸F-labeledradiopharmaceuticals and particularly, the production and use ofanhydrous ¹⁸F-containing gases for more efficient and cost effective¹⁸F-labeling compounds used in PET imaging.

2. Description of the Related Art

Compounds that are labeled with the radionuclide Fluorine-18 (¹⁸F) areused as diagnostic imaging agents in positron emission tomography (PET).For example, 2-[¹⁸F]fluoro-2-deoxy-D-glucose (FDG) is one tracer used inPET imaging. This molecule, labeled with ¹⁸F, behaves in a way similarto glucose in the first step of its destabilization in the human bodyand allows a user to map and quantify this fundamental mechanism. It isindicated for diagnosis of numerous diseases. FDG and its preparationare described in U.S. Pat. Nos. 4,617,386, 4,794,178, 5,169,942,5,264,570, 5,436,325, 5,759,513, 5,808,020, 5,932,178, and 6,172,207.

FDG and many other ¹⁸F-labeled compounds are used in clinical PETimaging of human diseases. However, the radiochemical synthesis of such¹⁸F-labeled compounds is often limited by the reactivity of the rawmaterial [¹⁸F]fluoride. Specifically, the difficulty in producing[¹⁸F]fluoride in an anhydrous form has been a major obstacle to theefficient syntheses of many commonly used PET tracers from tracerprecursor compounds.

Conventionally, PET precursor compounds are labeled with ¹⁸F using the[¹⁸F]fluoride ions produced when the accelerated protons produced by aproton accelerator such as a cyclotron target the ¹⁸O atoms in ¹⁸Oenriched water. The resulting [¹⁸F]fluoride ions are dissolved in thewater solution, and this water solution cannot be transported longdistances without sustaining high losses within the transport tubing.

The current processing methods for preparing and using [¹⁸F]fluoride for¹⁸F-labeling of PET tracer precursor compounds are time-consuming, incurloss of radioactivity, and present inflexibility for design of newradiosynthesis paradigms, such as the “chemistry-on-a-chip” model.Furthermore, the conventional model for manufacturing and distributing¹⁸F-labeled compounds, such as FDG, to hospitals for clinical PETimaging has been limited to a centralized distribution scheme wherebynetworks of PET tracer distributors ship FDG and other tracers tohospitals via trucks as a final product to be administered to patients.

A new “decentralized” distribution model has been proposed by othersthat entails distributing raw material [¹⁸F]fluoride to various PETimaging sites, such as hospitals, wherein each site would have dedicated¹⁸F radiochemistry equipment capable of converting the [¹⁸F]fluoride to¹⁸F-products according to a “dose-on-demand” model. This concept has notbeen put into practice because conventional radiochemistry methods donot efficiently convert [¹⁸F]fluoride in water solution into useful¹⁸F-products, such as PET tracer compounds.

Typically, [¹⁸F]fluoride is produced in a cyclotron target containing¹⁸O-enriched water, with enrichment of ¹⁸O exceeding 95%. In contrast,natural water contains only 0.2% enrichment of ¹⁸O. The enrichmentprocess is costly, resulting in high cost for ¹⁸O enriched water and thedesire to efficiently recycle the enriched water for reuse.

After the proton irradiation of the targeted ¹⁸O-enriched water iscompleted, the resulting [¹⁸F]fluoride-containing water is forced byoverpressure through Teflon or polypropylene tubing over long distances(20-60 feet) to radiochemistry hot cells, where further radiochemicalprocessing is performed. Because water naturally adheres to the tubing,there are unavoidable losses of [¹⁸F]fluoride associated with thetransport process. In most facilities, a rinse of the target with eithernormal water (mainly ¹⁶O-water) or ¹⁸O-enriched water is performed toobtain a large portion of the adhered [¹⁸F]fluoride, but this step hassignificant disadvantages related to the high cost of ¹⁸O-enriched waterand the limited cost savings associated with recycling.

The radiochemistry process, which occurs in a separate radiochemistryhot cell, generally begins by separating the [¹⁸F]fluoride from the¹⁸O-enriched water, typically using an anion-exchange cartridge.[¹⁸F]fluoride is trapped on the cartridge while the ¹⁸O-enriched wateris collected, stored and returned to the vendor for recycling.

If the target rinse is performed with ¹⁸O-enriched water, then the¹⁸O-enrichment of the water remains high, and the material is recycledwith minimal cost. However, the cost of the ¹⁸O water rinse issubstantial (typically more than $125). On the other hand, if normalwater is used for the rinse, then the isotopic enrichment of thecollected ¹⁸O water is compromised such that the collected water willhave much less value when sold back to the vendor.

The existing methods for preparing and transporting [¹⁸F]fluoride forlabeling PET tracer precursor compounds present a number of significantchallenges. As noted above, such methods result in significant loss ofthe [¹⁸F]fluoride raw material in transfer lines. Furthermore,significant radioactive decay occurs in the time needed to dry down the¹⁸F in the radiochemistry hot cell. In addition, because of the volumeof the ¹⁸O-enriched water within which the [¹⁸F]fluoride is delivered,current methods limit the potential designs that can be used forradiochemistry processing. For example, microfluidic processing cannotbe done with such large volumes (typically greater than 2 mL), and suchvolumes necessitate using a non-microfluidic ¹⁸F dry-down apparatus andprocedures. Similarly, transfer of [¹⁸F]fluoride used in conventionalmethods to a microfluidic chip involves significant challenges and largeloss of [¹⁸F]fluoride. Finally, the existing ¹⁸F-labeling technologiesoften leave the [¹⁸F]fluoride in the presence of trace metal ions thathinder its reactivity, thus further decreasing incorporation yields into¹⁸F-labeled radiopharmaceuticals.

Thus, there is a need for improved methods for preparing, transporting,and incorporating ¹⁸F-labels into PET tracer precursor compounds to makePET tracer compounds for clinical use.

SUMMARY OF THE INVENTION

The present invention provides methods and systems for preparing gaseous¹⁸F containing compounds for use in labeling PET precursor compoundswith ¹⁸F, as well as related compositions and compounds.

In one exemplary embodiment, the invention entails the conversion of[18F] fluoride produced by exposing ¹⁸O-enriched water to a cyclotronbeam of accelerated protons into a gaseous chemical form (i.e., agaseous ¹⁸F-compound) at close proximity to the cyclotron target. As aresult of this conversion to a gaseous ¹⁸F-compound, the¹⁸F-radioactivity can be effectively separated from the ¹⁸O-enrichedwater with minimal loss and then transported to radiochemical hot cellsthrough gas lines, again with minimal transport losses. Using thedisclosed method, the gaseous ¹⁸F-compounds can be produced from[¹⁸F]fluoride with greater than 95% efficiency.

As a non-limiting example, ¹⁸F acetyl fluoride, an exemplary gaseous¹⁸F-compound that can be produced using the disclosed method, has aboiling point of 21° C. It is therefore a gas at room temperature, andcan be easily transported through polymer tubing without impediment orloss of the attached ¹⁸F. Furthermore, it is stable at room temperature,can be readily converted back to [¹⁸F]fluoride in basic solutions, andcan also be converted directly to ¹⁸F-labeled products by reaction withPET tracer precursors to produce the corresponding PET tracer.

After transport from the cyclotron, the gaseous ¹⁸F-compounds can beeasily trapped in an organic solvent such as acetonitrile or on asolid-phase extraction cartridge as a first step in radiochemicalprocessing. By inclusion of a phase-transfer catalyst in the trappingsolution, the gaseous ¹⁸F-compounds can provide [¹⁸F]fluoride reactantsfor the nucleophilic substitution reactions used to synthesize a largenumber of ¹⁸F-labeled radiopharmaceuticals, including2-[¹⁸F]fluoro-2-deoxyglucose (FDG), the most common PET imagingradiopharmaceutical. The disclosed methods can potentially replace morecomplicated, costly, and time-consuming transport and production methodsassociated with ¹⁸F-labeling of radiopharmaceuticals.

Accordingly, in a first aspect, the disclosure encompasses a method forpreparing a gaseous ¹⁸F-compound for labeling a positron emissiontomography (PET) tracer precursor compound with ¹⁸F. The method includesthe steps of (1) contacting a composition comprising [¹⁸F]fluoride ionswith an anhydride having the formula:

wherein each R is independently a substituted or unsubstituted, straightchain or branched C₁-C₄ alkyl group. The two R groups may be the same,or they may be different. For example, the first R may be methyl and thesecond R may be tert-butyl. In the subsequent reaction, a gaseous¹⁸F-compound is produced having the formula:

In some other embodiments, the disclosure encompasses a method forpreparing a gaseous ¹⁸F-compound from [¹⁸F]fluoride ions produced by aproton accelerator. The method includes the steps of (1) contacting acomposition comprising the [¹⁸F]fluoride ions with an acyl halide havingthe formula:

wherein X is I, Br, or Cl, and each R is independently a substituted orunsubstituted, straight chain or branched C₁-C₄ alkyl group. In thesubsequent reaction, a gaseous ¹⁸F-compound is produced having theformula:

Preferably, the gaseous ¹⁸F-compound is anhydrous. In some embodiments,the step of contacting the composition comprising [¹⁸F]fluoride ionswith the anhydride or acyl halide occurs at a temperature of 50-70°Celsius.

In some embodiments, R is an alkyl group that is substituted with one ormore halogen atoms, such as, without limitation, fluorine or chlorine.In certain of these embodiments, R can be —CH₂F, —CH₂Cl or —CHFCH₃.

In some other embodiments, R is an unsubstituted alkyl group. In certainof these embodiments, R can be —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, or—C(CH₃)₃.

In some embodiments, the composition comprising the [¹⁸F]fluoride ionsfurther includes an anion-exchange resin on which the [¹⁸F]fluoride ionsare trapped. Optionally, the composition comprising [¹⁸F]fluoride ionstrapped on the anion-exchange resin is produced by contacting theanion-exchange resin with a water solution comprising [¹⁸F]fluoride ionsand subsequently drying the resin by rinsing with acetone followed by aflow of nitrogen. In some embodiments, the anion exchange resin is aweakly basic, macroporous anion exchange resin having beads of uniformsize, and may further comprise a styrene-divinylbenzene copolymer matrixand tertiary and quaternary ammonium groups. A preferred anion exchangeresin is a LEWATIT® MP-64 carbonate form resin.

In certain embodiments, the water solution comprising [¹⁸F]fluoride ionsis produced by contacting one or more accelerated protons with¹⁸O-enriched target water. In certain embodiments, the step ofcontacting one or more accelerated protons with the ¹⁸O-enriched targetwater is performed in close proximity to the step of contacting thecomposition comprising [¹⁸F]fluoride ions trapped on the anion-exchangeresin with the anhydride to produce the gaseous ¹⁸F-compound. In certainembodiments, the step of contacting one or more accelerated protons withthe ¹⁸O-enriched target water is performed within 15 feet of the step ofcontacting the composition comprising [¹⁸F]fluoride ions trapped on theanion-exchange resin with the anhydride to produce the gaseous¹⁸F-compound.

In certain embodiments, the steps of contacting one or more acceleratedprotons with the ¹⁸O-enriched target water and contacting thecomposition comprising [¹⁸F]fluoride ions trapped on the anion-exchangeresin with the anhydride to produce the gaseous ¹⁸F-compound are bothperformed within a cyclotron vault. In certain such embodiments, thegaseous ¹⁸F-compound is stored within the cyclotron vault.

In some embodiments, the gaseous ¹⁸F-compound is stored in amicrofluidic device. In some embodiments, the gaseous ¹⁸F-compound istransported to a radiochemistry hot cell, optionally via polymerictubing.

In some embodiments, the method further includes the step of contactingthe gaseous ¹⁸F-compound with a PET tracer precursor compound, wherebythe PET tracer precursor compound is labeled with ¹⁸F to produce an¹⁸F-labeled PET tracer compound. In some such embodiments, the¹⁸F-labeled PET tracer compound produced is 2-[¹⁸F]fluoro-2-deoxyglucose(FDG). In some such embodiments, the ¹⁸F-labeled PET tracer compoundproduced is [¹⁸F]tetrafluoroborate (BF₄ ⁻).

Some embodiments further include the step of contacting the gaseous¹⁸F-compound with a composition comprising an organic solvent, wherebythe gaseous ¹⁸F-compound is trapped within the composition. In some suchembodiments, the organic solvent is acetonitrile. Optionally, thecomposition comprising the organic solvent further comprises a phasetransfer catalyst, a PET tracer precursor compound, or both. Optionally,the phase transfer catalyst is tetraethylammonium bicarbonate.

In some embodiments, the method further includes the step of contactingthe gaseous ¹⁸F-compound with a second gas to form an ¹⁸F-labeledradioactive product. Optionally, the second gas is BF₃, and the¹⁸F-labeled radioactive product is [¹⁸F]BF₄ ⁻.

In a second aspect, the disclosure encompasses an ¹⁸F-compound havingthe formula:

wherein R is a substituted or unsubstituted, straight chain or branchedC₁-C₄ alkyl group, with the proviso that R is not —CH₃.

In some embodiments, R is an alkyl group that is substituted with one ormore halogen atoms, including without limitation fluorine or chlorine.In some such embodiments, R is —CH₂F, —CH₂Cl, or —CHFCH₃.

In some other embodiments, R is an unsubstituted alkyl group. In somesuch embodiments, R is —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, or —C(CH₃)₃.

In a third aspect, the disclosure encompasses a composition for labelinga positron emission tomography (PET) tracer precursor compound with ¹⁸F.the composition includes (1) an ¹⁸F-compound having the formula:

wherein R is a substituted or unsubstituted, straight chain or branchedC₁-C₄ alkyl group; and (2) an organic solvent.

In some embodiments, R is an alkyl group that is substituted with one ormore halogen atoms, such as without limitation, chlorine or fluorine. Insome such embodiments, R is —CH₂F, —CH₂Cl, or —CHFCH₃.

In some other embodiments, R is an unsubstituted alkyl group. In suchembodiments, R may optionally be —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,or —C(CH₃)₃.

In some embodiments, the organic solvent is acetonitrile.

In some embodiments, the organic solvent is tetrahydrofuran.

In some embodiments, the organic solvent is an alcohol (methanol,ethanol, etc.), whereby the gaseous [¹⁸F]fluoride immediately forms[¹⁸F]HF.

In some embodiments, the composition further includes a phase-transfercatalyst. Optionally, the phase transfer catalyst is tetraethylammoniumbicarbonate.

In some embodiments, the composition may further include a PET tracerprecursor compound.

In some embodiments, the gaseous [¹⁸F]fluoride is trapped on asolid-phase extraction cartridge. This can effectively concentrate thegaseous [¹⁸F]fluoride for subsequent elution by an organic solvent in asmall volume.

In some embodiments, the gaseous [¹⁸F]fluoride is trapped on asolid-phase extraction cartridge for transport of the ¹⁸F-radioactivityto a distant site as a solid substance that can be easily shielded. Atthe distant site, the acyl [¹⁸F]fluoride is eluted from the cartridgewith an organic solvent.

In some embodiments, the solid-phase extraction medium for trappinggaseous [¹⁸F]fluoride is Porapak N.

In some embodiments, the solid-phase extraction medium for trappinggaseous [¹⁸F]fluoride is Porapak Q.

In some embodiments, the solid-phase extraction medium for trappinggaseous [¹⁸F]fluoride is Oasis WAX.

In a fourth aspect, the disclosure encompasses a system for producing agaseous ¹⁸F-compound for labeling a positron emission tomography (PET)tracer precursor compound with ¹⁸F. The system includes ¹⁸O-enrichedtarget water; a proton accelerator configured to produce a beam ofaccelerated protons in contact with the target water at a targetlocation; an anion-exchange resin in close proximity to the targetlocation; a gaseous [¹⁸F]fluoride production apparatus that includes theadditional hardware needed to form the gaseous [¹⁸F]fluoride; and atransport tube capable of transporting a gas produced on the surface ofthe ion exchange resin to another location.

In some embodiments, the target location and the ion exchange resin areless than 15 feet apart and the gaseous [¹⁸F]fluoride productionapparatus is adjacent to the ion exchange resin.

In some embodiments, the proton accelerator is a cyclotron at leastpartially surrounded by the walls of a cyclotron vault, and the targetlocation, the ion exchange resin, and the first conduit are locatedinside of the walls of the cyclotron vault. In some such embodiments,the transport tube connects the gaseous ¹⁸Ffluoride production apparatusto a gas storage reservoir within the cyclotron vault.

In some embodiments, the transport tube is greater than twenty feet inlength and extends to the outside of the cyclotron vault. In some suchembodiments, the second conduit is capable of transporting the gas to aradiochemistry hot cell. In some such embodiments, the transport tube isgreater than sixty feet in length.

In some embodiments, the system further includes an anhydride having theformula:

wherein each R is independently a substituted or unsubstituted, straightchain or branched C₁-C₄ alkyl group.

In some embodiments, the transport tube contains a gaseous ¹⁸F-compoundhaving the formula:

wherein R is a substituted or unsubstituted, straight chain or branchedC₁-C₄ alkyl group. In some such embodiments, R is an alkyl group that issubstituted with one or more halogen atoms, such as without limitationchlorine or fluorine. In such embodiments, R is optionally —CH₂F,—CH₂Cl, or —CHFCH₃.

In other embodiments, R is an unsubstituted alkyl group. In some suchembodiments, R is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, or —C(CH₃)₃.

In a fifth aspect, the disclosure encompasses a system for producing agaseous ¹⁸F-compound for labeling a positron emission tomography (PET)tracer precursor compound with ¹⁸F. The system includes a reagentdelivery valve in communication with a source of ¹⁸F-fluoride and atleast one precursor for reacting with the ¹⁸F-fluoride to provide agaseous ¹⁸F-compound; a first bank including a first set of columns, aselected one of the first set of columns reversibly coupled to thereagent delivery valve; a second bank including a second set of columns,a selected one of the second set of columns reversibly coupled to theselected one of the first set of columns; and an output selector valvereversibly coupled to the selected one of the second set of columns forrecovery of the gaseous ¹⁸F-compound. Each of the first bank and thesecond bank are independently rotatable about an axis to couple any oneof the first set of columns in the first bank with any one of the secondset of columns in the second bank, and when each of the reagent deliveryvalve, the first bank, the second bank, and the output selector valveare coupled, a continuous fluid pathway is formed between the reagentdelivery valve and the output selector valve.

In some embodiments, the first set of columns are trap columns fortrapping the ¹⁸F-fluoride.

In some embodiments, the second set of columns are purifications columnsfor purifying the gaseous ¹⁸F-compound.

These and other features, aspects, and advantages of the presentinvention will become better understood upon consideration of thefollowing detailed description, drawings, and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is generic reaction scheme for the production of the disclosedgaseous ¹⁸F-compounds using acid anhydrides.

FIG. 1B is a specific reaction scheme for the production of ¹⁸F acetylfluoride from [¹⁸F]fluoride ion using acetic anhydride.

FIG. 1C is generic reaction scheme for the production of the disclosedgaseous ¹⁸F-compounds using acid halides.

FIG. 2 is a schematic drawing of an exemplary production, transport, anduse system for the disclosed gaseous ¹⁸F-compounds.

FIG. 3 is a schematic drawing of an exemplary production, transport, anduse system for the disclosed gaseous ¹⁸F-compounds, illustrating thetransportability of the ¹⁸F-compounds.

FIG. 4 is a schematic drawing of an exemplary centralized production anddecentralized use system for the disclosed gaseous ¹⁸F-compounds,illustrating the use of gaseous [¹⁸F]fluoride in a decentralized PETradiochemistry paradigm.

FIG. 5A is an image of an example system for producing gaseous¹⁸F-compounds according the present disclosure.

FIG. 5B is a schematic illustration of the example system of FIG. 5A.

FIG. 6 is a schematic illustration a reagent delivery valve of thesystem of FIG. 5B.

FIG. 7 is a schematic illustration an output selector valve of thesystem of FIG. 5B.

FIG. 8 is a schematic illustration showing a profile view along an axisof rotation of a first bank of columns and a second bank of columns ofthe system of FIG. 5B.

FIG. 9 is a schematic illustration of the first bank of columns of FIG.8 in isolation.

FIG. 10 is a schematic illustration of the second bank of columns ofFIG. 8 in isolation.

FIG. 11A is another schematic illustration of the example system of FIG.5A showing the system in a first, fully coupled state where a continuousfluid path extends from the reagent delivery valve to the outputselector valve.

FIG. 11B is a schematic illustration similar to FIG. 11A showing thesystem in a second, fully separated state where the fluid path betweenthe reagent delivery valve and the output selector valve is disruptedsuch that the first bank and the second bank may be independentlyrotated about a corresponding axis of rotation.

DETAILED DESCRIPTION OF THE INVENTION

In one exemplary embodiment, the disclosure encompasses a highlyefficient method to transport ¹⁸F isotope produced via the ¹⁸O (p,n)¹⁸Freaction facilitated by a proton accelerator such as a cyclotron. Inaddition to reducing the ¹⁸F loss associated with conventional transportusing [¹⁸F]fluoride, the method results in greater efficiency of usageof the raw material ¹⁸O-enriched water used to produce the ¹⁸F isotope.

Typically, [¹⁸F]fluoride is produced in a cyclotron target containing¹⁸O-enriched water with enrichment of ¹⁸O exceeding 95%. Natural watercontains only 0.2% enrichment of ¹⁸O. The enrichment process is costly,resulting in high cost of ¹⁸O-enriched water, and the desire to reuse(recycle) the material. After the proton irradiation is completed, the¹⁸F-containing water is forced by overpressure through Teflon orpolypropylene tubing a long distance (20-60 feet) to radiochemistry hotcells where further radiochemical processing is performed.

Since water naturally adheres to the tubing, there are unavoidablelosses of ¹⁸F associated with the transport process. In most facilities,a rinse of the target with either normal water (mainly ¹⁶O-water) or¹⁸O-enriched water is performed to obtain a large portion of the adhered¹⁸F-radioactivity, but this step has significant disadvantages relatedto the high cost of ¹⁸O-enriched water and the cost savings associatedwith recycling.

The radiochemistry process starts with a process of separating the[¹⁸F]fluoride from the ¹⁸O-enriched water, typically using ananion-exchange cartridge. [¹⁸F]fluoride is trapped on the cartridgewhile the ¹⁸O-enriched water is collected, stored and sold back to thevendor for recycling. If the target rinse is performed with ¹⁸O-enrichedwater, then the ¹⁸O-enrichment of the water remains high, and thematerial remains useful for recycling. However, the cost of the ¹⁸Owater rinse is substantial (typically >$125). On the other hand, ifnormal water is used for the rinse, then the isotopic enrichment of thecollected ¹⁸O water is compromised such that the collected water willhave much less value to be sold back to the vendor for recycling.

In an exemplary embodiment, the invention entails the conversion of[¹⁸F]fluoride to a gaseous chemical form (a gaseous ¹⁸F-compound) atclose proximity to the cyclotron target so that the ¹⁸F-radioactivitycan be effectively separated from the ¹⁸O-enriched water with minimallosses and then transported to radiochemical hot cells through gaslines, again with minimal transport losses.

Referring first to FIG. 1A, the gaseous ¹⁸F-compound is produced bycontacting a composition containing the [¹⁸F]fluoride with an anhydridehaving the formula shown below the leftmost arrow. Each R isindependently a substituted or unsubstituted, straight chain or branchedC₁-C₄ alkyl group, and the R groups may be the same or different. Theresulting reaction produces the gaseous ¹⁸F-compound having the formulashown in the center. Optionally, the composition is first dried byacetone and nitrogen, and the gaseous ¹⁸F-compound may be trapped in asolid phase extraction medium, such as Porapak Q, as illustrated by therightmost arrow.

One specific exemplary gaseous ¹⁸F-compound produced by the method is¹⁸F-labeled acetyl fluoride ([¹⁸F]AcF), although the invention is notlimited to use of this chemical form. The production of [¹⁸F]AcF usingacetic anhydride is illustrated in FIG. 1B with R=CH₃. Gaseous [¹⁸F]AcFis produced from [¹⁸F]fluoride in greater than 95% efficiency using thedisclosed process. Acetyl fluoride has a boiling point of 21° C. It istherefore a gas at room temperature, and easily transported throughpolymer tubing.

Referring now to FIG. 1C, the gaseous ¹⁸F-compound can alternatively beproduced by contacting a composition containing the [¹⁸F]fluoride withan acid halide having the formula shown below the leftmost arrow. Each Ris independently a substituted or unsubstituted, straight chain orbranched C₁-C₄ alkyl group, and the R groups may be the same ordifferent. The resulting reaction produces the gaseous ¹⁸F-compoundhaving the formula shown in the center. Optionally, the composition isfirst dried by acetone and nitrogen, and the gaseous ¹⁸F-compound may betrapped in a solid phase extraction medium, such as Porapak Q, asillustrated by the rightmost arrow.

After transport from the cyclotron, [¹⁸F]AcF is easily trapped in anorganic solvent such as acetonitrile as a first step in radiochemicalprocessing. By including a phase-transfer catalyst in the trappingsolution, [¹⁸F]AcF provides [¹⁸F]fluoride for nucleophilic substitutionreactions for synthesis of a large number of ¹⁸F-labeledradiopharmaceuticals, including 2-[¹⁸]fluoro-2-deoxyglucose (FDG), themost common PET imaging radiopharmaceutical.

Referring now to FIG. 2, in an exemplary embodiment of the disclosedmethod, the [¹⁸F]fluoride is first converted to a gaseous ¹⁸F-compound,such as [¹⁸F]AcF (FIG. 2, A), with efficient collection of ¹⁸O-enrichedwater for recycling (FIG. 2, left box). The target may be rinsed withnormal water, but since there is minimal tubing volume between thetarget and the conversion module, the target and lines can be quicklydried to avoid loss of enrichment of the collected ¹⁸O-enriched water.

In a second optional step, the gaseous ¹⁸F-compound can be stored in avessel within the vault for distribution to multiple processes.

In a third step, the gaseous ¹⁸F-compound, such as [¹⁸F]AcF, istransported through polymer tubing to the radiochemistry hot cell (FIG.2, center). The transport process may be driven by an inert sweep gassuch as nitrogen. Losses of gaseous radioactivity in the polymer tubingare minimal.

In a fourth step, the gaseous ¹⁸F-compound, such as [¹⁸F]AcF, is trappedin an organic solvent and subsequently reacted with a substratecontaining a reactive leaving group to form a new C-¹⁸F bond, resultingin a new ¹⁸F-labeled compound (FIG. 2, B). A phase-transfer catalyst,such as tetraethylammonium bicarbonate, can help facilitate thisreaction.

Alternatively, the gaseous ¹⁸F-compound could be reacted with anothergas in the gas phase to form new radioactive products. In a non-limitingexample, [¹⁸F]AcF is reacted with BF₃ to form acetyl [¹⁸F]BF₄ ⁻.

The gaseous ¹⁸F-compound can be trapped within a microfluidic device toallow ¹⁸F radiochemistry to be done within small processing volumes.Further reaction of the ¹⁸F and radiochemical processing would proceedaccording to known conventional methods.

As illustrated in FIG. 3, in an alternative embodiment, the gaseous¹⁸F-compound is loaded onto a [¹⁸F]GF trap, which can then be shieldedand safely transported and subsequently unloaded to the synthesizer.

The disclosed method presents a number of advantages over usingconventional ¹⁸F processing methods. First, because of the drasticallydecreased transport losses between the production site (the cyclotrontarget) and the radiochemistry reactor (the radiochemistry hot cell),the disclosed method results in more efficient use of the [¹⁸F]fluorideproduced in the cyclotron target and facilitates longer transportdistances of ¹⁸F to the radiochemistry hot cell. Typically,[¹⁸F]fluoride in water cannot be delivered more than 60 feet in tubingwithout incurring significant losses. ¹⁸F losses are directlyproportional to transport tubing length, and can be as high as 30% whenusing conventional [¹⁸F]fluoride solutions. The use of gaseous¹⁸F-compounds instead of conventional [¹⁸F]fluoride solutions totransport the ¹⁸F virtually eliminates such losses.

Second, the disclosed method facilitates the highly efficient use ofcostly ¹⁸O-enriched water. Because the gaseous ¹⁸F-compound is producedin close proximity to the cyclotron target, and because the aqueous[¹⁸F]fluoride solution containing the ¹⁸O-enriched water need not betransported long distances to the radiochemistry hot cell, successfulrecycling of the ¹⁸O-enriched water is easier and more cost-effective.

Third, the gaseous ¹⁸F-compounds produced by the method exhibitincreased ¹⁸F reactivity. The anhydrous nature of the gaseous¹⁸F-compounds enhances the nucleophilicity of the attached[¹⁸F]fluoride, making the compounds highly reactive radiofluorinationagents. Accordingly, the gaseous ¹⁸F-compounds facilitate increasedradiofluorination yields. Improvement in yields make practical thesynthesis of certain compounds that have very poor yields usingconventional methods, thus providing facile access to certain¹⁸F-labeled radiopharmaceuticals that may be difficult to make usingconventional aqueous [¹⁸F]fluoride.

Furthermore, because of ease of synthesis when using the gaseous¹⁸F-compound s, the disclosed method provides access to newradiochemistry platforms and compounds. For example, thetracer-on-demand approach, which requires a source of ¹⁸F and utilizeschemistry-on-a-chip technology, has been in development for over tenyears, but has not reached its full potential, because of thetechnological difficulties involved in concentrating and drying[¹⁸F]fluoride in water. The disclosed gaseous [¹⁸F]fluoride technologycan provide reactive ¹⁸F for such fluorination platforms. Specifically,the disclosed gaseous ¹⁸F-compounds may be trapped under low temperaturein a very small volume on a microfluidics chip. The subsequent steps ofsynthesizing FDG and other ¹⁸F-compounds on a microfluidics chip havealready been developed and demonstrated, and are well-known in the art.

Fourth, the disclosed method simplifies the radiochemistry process byeliminating the ¹⁸F “dry-down” step in the radiochemical synthesis. Thetypical “dry-down” step, which is performed within the radiochemicalmodule, is necessary when using conventional radiofluorination, becausethe [¹⁸F]fluoride source material is provided in a water solution.However, the dry-down step requires time and incurs further ¹⁸F lossesin a dry-down reactor or microfluidic [¹⁸F]fluoride concentrator. In thedisclosed method, the ¹⁸F is converted to an anhydrous gaseous form inclose proximity to the proton accelerator, and the ¹⁸F is provided tothe radiochemical module in this form. This eliminates the need for thedry-down step.

Fifth, the faster ¹⁸F transport and radiochemical processing facilitatedby the disclosed method, together the increased reactivity of thefluorinating agent, will result in higher overall production yields of¹⁸F radiopharmaceuticals.

Sixth, the disclosed method will facilitate the conversion of gaseousfluoride to other gaseous products, or reaction in the gas phase to formnongaseous ¹⁸F-products. The reactivity of the ¹⁸F gaseous fluoridecompound will allow gas phase reactions with reactive substrates (e.g.BF₃).

Seventh, the ease of trapping and storing the gaseous ¹⁸F-compounds ofthe disclosed method enables practical storage and use-on-demand,eliminating the need to run the cyclotron to make ¹⁸F isotope for eachsynthesis. Using the disclosed method, a large batch of gaseous ¹⁸F canbe synthesized, stored in a shielded container in the cyclotron vault,and then partitioned out as needed to a number of radiochemistryprocesses throughout the day. In one exemplary centralized productionand decentralized use system, centrally produced gaseous [¹⁸F]fluoridecan be distributed to multiple decentralized PET radiochemistrylocations for making PET tracers for use as needed (see FIG. 4).

Gas lines can be easily piped to each radiochemistry hot cell and asimple shut-off valve used to control the amount of gaseous delivered tothe hot cell. After the desired amount is obtained by trapping in asolution located in a dose calibrator, if necessary, the remainder inthe line can be pushed back into the reservoir within the cyclotronvault. As an alternative, the disclosed gaseous ¹⁸F-compounds can bereadily trapped within a microfluidic device.

Finally, the disclosed method will result in lower maintenance costs for¹⁸F delivery lines and valves. Typically, the ¹⁸F water delivery linesmust be replaced every three to six months, depending on usage levels.Because the radioactivity concentration of the disclosed gaseous¹⁸F-compounds would be much less than for conventional aqueous[¹⁸F]fluoride deliveries, the polymer delivery lines will incur muchless radiation damage over the same period of time. Alternativematerials for the transfer lines can be considered for the gaseous¹⁸F-compounds such as stainless steel, since [¹⁸F]fluoride adherence tothese materials is no longer a consideration. Furthermore, the targetwater, which is included in conventional aqueous [¹⁸F]fluoridedeliveries, contains trace metals from the target that eventually canbuild up in the delivery lines and cause problems in valves. Incontrast, the disclosed anhydrous gaseous ¹⁸F-compounds do not containsuch trace metals.

EXAMPLES Example 1: Production and Use of Gaseous ¹⁸F Acetyl Fluoride

Materials, Methods, and Results.

¹⁸O-enriched target water was exposed to a beam of accelerated protonsproduced by a cyclotron. The resulting [¹⁸F]fluoride solution was passedthrough an anion-exchange column (using 100 mg Lewatit® MP-64 carbonateform ion-exchange resin) held at a temperature of 60° C. The[¹⁸F]fluoride trapping efficiency of this anion-exchange resin wasdetermined to be greater than 98%.

After passing through the anion-exchange column, the ¹⁸O-enriched waterwas collected for recycling. The target was rinsed with deionized water,and the rinse water was also passed through the anion-exchange column,but was not collected with the ¹⁸O-enriched water. The target and thelines leading to the anion-exchange column were subsequently dried underhelium.

The anion-exchange resin was then rinsed with 10 mL acetone, andsubsequently dried under nitrogen for 90 s. The anion-exchange resin wasthen wetted with acetic anhydride (0.25 mL) and allowed to react for 3minutes at 60° C. to form acetyl [¹⁸F]fluoride ([¹⁸F]AcF).

Nitrogen was then swept through the anion-exchange column to carry the[¹⁸F]AcF through a purification cartridge containing 1 g Porapak Q and 1g anhydrous sodium sulfate. After passing through the purificationcartridge, the [¹⁸F]AcF is swept under nitrogen through polymeric tubingto the radiochemistry hot cell. The [¹⁸F]AcF was trapped by bubbling itthrough a solution of acetonitrile at 0-20° C., or trapped on a PorapakN (100 mg) cartridge. Typical yields of [¹⁸F]AcF were 85%, uncorrectedfor radioactive decay. Optionally, the acetonitrile solution contains aphase-transfer catalyst, such as tetraethylammonium bicarbonate, and/ora radiolabeling precursor.

Example 2: Production and Use of Other Gaseous ¹⁸F Fluoride Compounds

In this example, we report the production of other ¹⁸F gaseous fluoridecompounds, including propanoyl [¹⁸F]fluoride, butanoyl [¹⁸F]fluoride,isobutanoyl [¹⁸F]fluoride, 2-[¹⁹F]fluoroacetyl [¹⁸F]fluoride,2-[¹⁹F]fluoropropanoyl [¹⁸F]fluoride, and chloroacetyl [¹⁸F]fluoride.The results are compared with those reported above for the production of[¹⁸F]AcF. For example, propanoyl [¹⁸F]fluoride was prepared by themethod described in Example 1, however, propionic anhydride (0.25 mL)was added to the MP-64 resin after trapping of [¹⁸F]fluoride and dryingwith acetone and nitrogen.

Example 3: Trapping of Gaseous Acetyl [¹⁸F]Fluoride on Porapak NCartridge

After production and purification of [¹⁸F]AcF as described in Example 1,it is swept under nitrogen to a cartridge containing 150 mg Porapak Nresin, thereby trapping the [¹⁸F]AcF with >98% efficiency. The [¹⁸F]AcFis subsequently eluted from the Porapak N cartridge with an organicsolvent, such as tetrahydrofuran or acetonitrile.

Example 4: Trapping of Gaseous ¹⁸F Acetyl Fluoride on Oasis WAXCartridge

After production and purification of [¹⁸F]AcF as described in Example 1,it is swept under nitrogen to a cartridge containing 100 mg Oasis WAXresin, thereby trapping the [¹⁸F]AcF with >98% efficiency. The [¹⁸F]AcFis subsequently eluted from the Porapak N cartridge with an organicsolvent, such as tetrahydrofuran or acetonitrile.

Example 5: Trapping of Gaseous Acetyl [¹⁸F]Fluoride in Stainless Steelor Polypropylene (PP) Tubing at Low Temperature

After production and purification of acetyl [¹⁸F]fluoride as describedin Example 1, it was swept under nitrogen through a 40 cm loop ofstainless steel tubing or polypropylene (PP) tubing (⅛ inch OD, 1/16inch ID) in a liquid nitrogen-ethanol bath (−116° C.) thereby trappingthe acetyl [¹⁸F]fluoride within the tubing with >98% efficiency.

Example 6: Trapping of Gaseous Propanoyl [¹⁸F]Fluoride in StainlessSteel or Polypropylene (PP) Tubing at Low Temperature

After production and purification of propanoyl [¹⁸F]fluoride asdescribed in Example 2, it was swept under nitrogen through 40 cmstainless steel tubing or polypropylene (PP) tubing (⅛ inch OD, 1116inch ID) in a dry ice-acetone bath (−78° C.) thereby trapping thepropanoyl [¹⁸F]fluoride within the tubing with >98% efficiency.

Example 7: Acyl [¹⁸F]Fluorides as Novel Synthons for Radiofluorination

This example provides additional data obtained using the general methodsoutlined previously.

Objectives.

Current methods for delivery, extraction, and reformulation of[¹⁸F]fluoride from proton-irradiated ¹⁸O-enriched water are far fromideal. We have developed gaseous acyl [¹⁸F]fluorides as novel synthonsthat offer the ability to transfer [¹⁸F]fluoride through gas lines in ananhydrous form.

Methods.

[¹⁸F]fluoride in ¹⁸O-enriched water was trapped on an anion-exchangecartridge (MP-64, 40 mg) maintained at 70° C. The cartridge was rinsedwith acetone and dried under nitrogen. Acetic or propionic anhydridewere added to the cartridge and allowed to react for 3 min, producingacetyl [¹⁸F]fluoride (AcF, Bp=21° C.) or propanoyl [¹⁸F]fluoride (PrF,Bp=43° C.), respectively. The gaseous acyl [¹⁸F]fluorides were swept bynitrogen from the MP-64 cartridge through an empty cartridge and twocartridges filled with Porapak-Q medium (900 mg each) maintained at30-40° C. The product was then transported through polypropylene (PP)tubing to a distant radiochemistry location. The acyl [¹⁸F]fluorideswere efficiently trapped in acetonitrile and other polar organicsolvents for subsequent radiofluorinations.

Results.

The unoptimized yields of purified acyl [¹⁸F]fluorides were 60-75%uncorrected. Radiochemical purity was confirmed as >99% by GC-FID whichis sensitive to radioactivity. Chemical purity was also >99% as shown byGC-FID. [¹⁸F]AcF was transported through 15 m of PP tubing (0.79 mm ID)with <0.9% adsorbance to the tubing. Adsorbance of [¹⁸F]PrF to PP tubingwas significantly higher (3.8% over 15 m). ¹⁸F-fluorination of themannose triflate FDG precursor in acetonitrile at 80° C. was >90% afteraddition of 10 mg tetraethylammonium bicarbonate to release the[¹⁸F]fluoride into solution.

Conclusions.

¹⁸F-labeled acyl fluorides were efficiently produced by a method thatlends itself to automation. The anhydrous nature of acyl [¹⁸F]fluoridesmay be advantageous for water-sensitive reactions. Furthermore, theirgaseous form may inspire new paradigms for distribution and utilizationof [¹⁸F]fluoride.

Example 8: Automated Production of ¹⁸F-Labeled Acyl Fluorides as¹⁸F-Fluorination Synthons

Presence of trace water and metal impurities in preparations of¹⁸F-fluoride can compromise radiofluorination efficiencies. Gaseous¹⁸F-acyl fluorides represent a source of anhydrous, reactive¹⁸F-fluoride. Accordingly, a system for high-yield, automated productionof ¹⁸F-acetyl fluoride (¹⁸F-AcF) or ¹⁸F-propanoyl fluoride (¹⁸F-PrF) wasdeveloped.

With reference to FIGS. 5-11, an automated module 20 was developed toproduce gaseous ¹⁸F-acyl fluorides via the reaction of ¹⁸F-fluoride withacetic anhydride or propanoyl anhydride for production of ¹⁸F-AcF or¹⁸F-PrF, respectively. The module 20 includes two sets of disposablecolumns arranged radially about an axis of rotation of a cylindricalbarrel or bank. A first bank 22 having an axis of rotation A₁ includescolumns 24. In one example the columns 24 are MP-64 columns (130-140 mg)for trapping of ¹⁸F-fluoride with recovery of ¹⁸O-water and reaction toproduce ¹⁸F-acyl fluorides. A second bank 26 includes columns 28. In oneexample, columns 28 are purification columns of Porapak Q (1 g) andsodium sulfate (1 g). The bank 22 and the bank 26 have a cylindrical“gun revolver” geometry that provides for at least about 12 runs from asingle setup of the module 20 depending on the number of columns 24 andcolumns 28 included in each of the bank 22 and the bank 26. Multipleoutput lines including output line 30 are accommodated.

The module 20 further includes a fluid flow path extending at leastbetween a reagent delivery unit 32 and an output collection unit 34. Thereagent delivery unit 32 includes a reagent delivery valve 36 that canbe placed in fluid communication with the first bank 22 via a fitting 38intermediate the valve 34 and the first bank 22. The first bank 22 canbe placed in fluid communication with the second bank 26 via anintermediate fitting 40. Further, the second bank 26 can be placed influid communication with the output collection unit 34 via a fitting 44and an output selector valve 42. When the components of the module 20are fully coupled together (see FIG. 11A), a continuous fluid pathextends from the reagent delivery unit 32 including the reagent deliveryvalve 36, through the fitting 38, a selected one of the columns 24 inthe first bank 22, the intermediate fitting 40, a selected one of thecolumns 28 in the second bank 26, the fitting 44, and the outputselector valve 42 of the output collection unit 34. However, when thecomponents of the module 20 are separated (i.e., not in fluidcommunication; see FIG. 11B), each of the first bank 22 and the secondbank 26 may be independently rotated about the corresponding axis ofrotation to align a selected one of the columns 24 of the first bank 22with a selected one of the columns 28 of the second bank 24 along theaxis A₃. The first bank 22 is rotatable along the axis A₁ with a rotaryunit 46. The second bank 26 is rotatable along the axis A₂ with a rotaryunit 48. In one example, the rotary unit 46 and the rotary unit 48 maybe electric motors.

Turning to FIG. 6, the reagent delivery valve 36 can be a selector valveoperable to select between two or more sources. For example, the reagentdelivery valve 36 can include a number of independently selectable ports50. In one example, a first port 50 a can be in fluid communication witha source 52 of a first precursor chemical (e.g., acetic anhydride), asecond port 50 b can be in fluid communication with a source 54 of asecond precursor chemical (e.g., propanoyl anhydride or ¹⁸F-Fluoride),and a third port 50 c can be in fluid communication with a source of awash chemical (e.g., acetone). The reagent delivery valve 36 can furtherbe in communication with a source of an inert gas (e.g., N₂), include apressure monitor, or a combination thereof.

With reference to FIG. 7, the output selector valve 42 can be a selectorvalve operable to select between two or more sources. For example, theoutput selector valve 42 can include a number of independentlyselectable ports 58. In one example, a first port 58 a can be in fluidcommunication with a waste collection tank 60 for recovery of a firstmaterial (e.g., ¹⁸O water), a second port 58 b can be in fluidcommunication with a collection tank 62 for recovery of a secondmaterial (e.g., ¹⁶O waste water), and a third port 58 c can be in fluidcommunication with a collection tank 64 for recovery of a waste stream.The output selector valve 36 can further be in communication with acollection tank or another vessel, analytical unit, or instrument forcollection or use of a product stream.

FIGS. 8-10 show that the first bank 22 can include a number of radiallyarranged columns 24, while the second bank 26 can include a number ofradially arranged columns 28. The columns 24 can be single use columnsfor absorbing and reacting precursors, while the columns 28 cansimilarly be single use columns for purification of the products formedin the first bank 22. In one aspect, one or more of the columns 24 andthe columns 28 may be substituted for or used as waste columns, cleaningcolumns, recover ports, empty chambers, the like, and combinationsthereof. For example, the column 24 a and the column 28 a (or thechamber in the bank 22 or the bank 26 for containing the column 24 a orthe column 28 a, respectively) may be used to for collecting wastematerial or for flowing waste material through the module 20. Further,the second bank 26 can be designed to accommodate a thermocouple (notshown) in a thermocouple slot 66 or a heating cartridge (not shown) forcontrolling the temperature of the columns 28 in a heating cartridgeslot 68.

Turning now to FIGS. 11A and 11B, a first linear actuator 70 is operableto slide or translate the at least one of the fitting 38, the first bank22, and the intermediate fitting 40 along a path that is parallel to theaxis A₃. In another aspect, a second linear actuator 72 is operable toslide or translate at least one of the fitting 44, the second bank 26,and the intermediate fitting 40 along an axis parallel to the axis A₃.In one embodiment, the intermediate fitting 40 may be held in a fixedposition, while the first linear actuator 70 may be coupled to thefitting 38 and the first bank 22, and the second linear actuator 72 maybe coupled to the fitting 44 and the second bank 26. Operation of thefirst linear actuator 70 may guide (pull) the first bank 22 away fromthe intermediate fitting 40, thereby disconnecting the first bank 22from the intermediate fitting 40. Subsequently, the first linearactuator 70 may guide (pull) the fitting 38 away from the first bank 22,thereby disconnecting the first bank 22 from the fitting 38. In oneaspect, stops (not shown) may be include to prevent the continuedtranslation of the first bank 22 in order to disconnect the first bank22 from the fitting 38. Similarly, operation of the second linearactuator 72 may guide (pull) the second bank 26 away from theintermediate fitting 40, thereby disconnecting the second bank 22 fromthe intermediate fitting 40. Subsequently, the second linear actuator 72may guide (pull) the fitting 44 away from the second bank 26, therebydisconnecting the second bank 26 from the fitting 44. Stops (not shown)may be included to prevent the continued translation of the second bank26 in order to disconnect the second bank 26 from the fitting 44.

In one example, purified ¹⁸F-AcF was trapped in anhydrous polar organicsolvents such as acetonitrile, or on solid-phase extraction cartridgessuch as Oasis WAX, or in a cooled tubing loop at −40° C. to −80° C. Anacetone rinse cycle was used between runs. ¹⁸F-AcF was produced indecay-corrected radiochemical yields of 93.3±5.3% in 20-25 min. Furtherreductions of production time are anticipated. Radiochemical puritywas >99% by radio-GC. Radiochemical stability of ¹⁸F-AcF was >99% to atleast 4 h post-production. ¹⁸F-AcF was readily transported in nitrogenthrough 15 m of 0.8 mm ID polypropylene tubing with low (0.64±0.12%)adsorption to the tubing. Following dissolution of ¹⁸F-AcF inacetonitrile containing the phase-transfer catalyst tetraethylammoniumbicarbonate and various labeling precursors, both aliphatic and arylradiofluorinations were achieved in medium to high yields. Aftermeasurement of the limit of detection for AcF, the specific activity wasestimated to be >1.3 GBq/umol with a starting radioactivity of 1.5 GBq.

¹⁸F-acyl fluorides represent a new paradigm for preparation andtransport of anhydrous, reactive ¹⁸F-fluoride as raw material forradiofluorinations. The automated module opens the possibility forproduction of highly transportable ¹⁸F-acyl fluorides near to thecyclotron and highly efficient transport of ¹⁸F-fluoride in the gasphase. Furthermore, this overcomes limitations imposed by transport of¹⁸F-fluoride in water and the required maintenance of the isotopedelivery lines.

The present invention has been described in terms of one or morepreferred embodiments, and it should be appreciated that manyequivalents, alternatives, variations, and modifications, aside fromthose expressly stated, are possible and within the scope of theinvention.

Each reference identified in the present application is hereinincorporated by reference in its entirety.

While present inventive concepts have been described with reference toparticular embodiments, those of ordinary skill in the art willappreciate that various substitutions and/or other alterations may bemade to the embodiments without departing from the spirit of presentinventive concepts. Accordingly, the foregoing description is meant tobe exemplary, and does not limit the scope of present inventiveconcepts.

A number of examples have been described herein. Nevertheless, it shouldbe understood that various modifications may be made. For example,suitable results may be achieved if the described techniques areperformed in a different order and/or if components in a describedsystem, architecture, device, or circuit are combined in a differentmanner and/or replaced or supplemented by other components or theirequivalents. Accordingly, other implementations are within the scope ofthe present inventive concepts.

INDUSTRIAL APPLICABILITY

The invention relates to the manufacture of radiopharmaceuticals andparticularly, the manufacture of ¹⁸F-containing PET tracers for clinicaluse using gaseous ¹⁸F-compounds instead of aqueous [¹⁸F]fluoride as thesource of the ¹⁸F-label.

1. A method for preparing a gaseous ¹⁸F-compound for labeling a positronemission tomography (PET) tracer precursor compound with ¹⁸F, the methodcomprising: contacting a composition comprising [¹⁸F]fluoride ions withan anhydride having the formula:

wherein each R is independently a substituted or unsubstituted, straightchain or branched C₁-C₄ alkyl group; whereby a gaseous ¹⁸F-compound isproduced having the formula:


2. A method for preparing a gaseous ¹⁸F-compound for labeling a positronemission tomography (PET) tracer precursor compound with ¹⁸F from[¹⁸F]fluoride ions produced by a proton accelerator, the methodcomprising: contacting a composition comprising [¹⁸F]fluoride ions withan acyl halide having the formula:

wherein X is I, Cl, or Br; and wherein R is a substituted orunsubstituted, straight chain or branched C₁-C₄ alkyl group; whereby agaseous ¹⁸F-compound is produced having the formula:


3. The method of claim 1, wherein the gaseous ¹⁸F-compound is anhydrous.4. The method of claim 1, wherein the step of contacting the compositioncomprising [¹⁸F]fluoride ions with the anhydride occurs at a temperatureof 50-70° Celsius.
 5. The method of claim 1, wherein R is an alkyl groupthat is substituted with one or more halogen atoms.
 6. The method ofclaim 5, wherein the one or more halogen atoms are selected from thegroup consisting of fluorine and chlorine.
 7. The method of claim 6,wherein R is selected from the group consisting of —CH₂F, —CH₂Cl, and—CHFCH₃.
 8. The method of claim 1, wherein R is an unsubstituted alkylgroup.
 9. The method of claim 8, wherein R is selected from the groupconsisting of —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, and —C(CH₃)₃. 10.The method of claim 9, wherein R is —CH₃.
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 55. A system for producing a gaseous¹⁸F-compound for labeling a positron emission tomography (PET) tracerprecursor compound with ¹⁸F, the system comprising: ¹⁸O-enriched targetwater; a proton accelerator configured to produce a beam of acceleratedprotons in contact with the target water at a target location; ananion-exchange resin in close proximity to the target location; agaseous [¹⁸F]fluoride production apparatus comprising the additionalhardware needed to produce the gaseous ¹⁸F-compound; and a transporttube capable of transporting a gas produced on the surface of the ionexchange resin to another location.
 56. The system of claim 55, whereinthe target location and the ion exchange resin are less than fifteenfeet apart and the gaseous [¹⁸F]fluoride production apparatus isadjacent to the ion exchange resin.
 57. The system of claim 55, whereinthe proton accelerator is a cyclotron at least partially surrounded bythe walls of a cyclotron vault, and wherein the target location, the ionexchange resin, and the gaseous [¹⁸F]fluoride production apparatus arelocated inside of the walls of the cyclotron vault.
 58. The system ofclaim 57, wherein the transport tube is connected to a gas storagereservoir within the cyclotron vault.
 59. The system of claim 57,wherein the transport tube is greater than twenty feet in length andextends to the outside of the cyclotron vault.
 60. The system of claim59, wherein the transport tube is capable of transporting the gas to aradiochemistry hot cell.
 61. The system of claim 60, wherein thetransport tube is greater than sixty feet in length.
 62. The system ofclaim 55, further comprising an anhydride having the formula:

or an acyl halide having the formula:

wherein X is I, Cl, or Br, and wherein each R is independently asubstituted or unsubstituted, straight chain or branched C₁-C₄ alkylgroup.
 63. The system of claim 55, wherein the transport tube contains agaseous ¹⁸F-compound having the formula:

wherein R is a substituted or unsubstituted, straight chain or branchedC₁-C₄ alkyl group.
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 73. The method of claim 2, wherein the gaseous¹⁸F-compound is anhydrous.
 74. The method of claim 2, wherein the stepof contacting the composition comprising [¹⁸F]fluoride ions with theanhydride occurs at a temperature of 50-70° Celsius.
 75. The method ofclaim 2, wherein R is an alkyl group that is substituted with one ormore halogen atoms.
 76. The method of claim 75, wherein the one or morehalogen atoms are selected from the group consisting of fluorine andchlorine.
 77. The method of claim 76, wherein R is selected from thegroup consisting of —CH₂F, —CH₂Cl, and —CHFCH₃.
 78. The method of claim2, wherein R is an unsubstituted alkyl group.
 79. The method of claim78, wherein R is selected from the group consisting of —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, and —C(CH₃)₃.
 80. The method of claim 79, whereinR is —CH₃.